Hyperkalemia
Conditions
Keywords
treatment of hyperkalemia, chronic kidney disease, hypertension, hyperkalemia, potassium, spironolactone, heart failure, Renin Angiotensin-Aldosterone System Inhibitor (RAASi), RAASi, high potassium, eplerenone, reduced ejection fraction
Brief summary
The purpose of this study is to assess the effects of patiromer compared with placebo on serum K+ in HF patients.
Detailed description
Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, randomized withdrawal, parallel group study that includes screening and up to 12 weeks Run-in Phase (all subjects will have patiromer initiated and RAASi medications, including mineralocorticoid receptor antagonist (MRA) optimized) and a randomized withdrawal Blinded Treatment Phase. The study population includes subjects with heart failure (HF) with reduced ejection fraction (HFrEF) who are hyperkalemic (serum potassium \[K+\] \> 5.0 mEq/L) while receiving treatment with renin angiotensin aldosterone system inhibitor (RAASi) medications or who are normokalemic (serum K+ 4.0 - 5.0 mEq/L) but have a history of hyperkalemia prior to screening with subsequent reduction or discontinuation of a RAASi medication. Each subject's participation includes a Run-in Phase (maximum 12 weeks) followed by the Treatment Phase (variable per subject). Study duration for individual subjects will vary, depending on their individual enrollment date. Subjects who prematurely discontinue patiromer/placebo will remain in the study for the collection of clinical events data and will receive usual care.
Interventions
DRUGPatiromer
The starting dose of patiromer will be 1 packet/day and may be taken either with food or without food. Based upon the patiromer treatment algorithm patiromer may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, patiromer may be decreased to a minimum of 0 packets/day. Doses of patiromer will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
DRUGPlacebos
The starting dose of placebo will be 1 packet/day and may be taken either with food or without food. Based upon the placebo treatment algorithm placebo may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, placebo may be decreased to a minimum of 0 packets/day. Doses of placebo will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
Sponsors
Syneos Health
Vifor Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, randomized withdrawal, parallel group study that includes screening and 12 weeks Run-in Phase and a randomized withdrawal Blinded Treatment Phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age at least 18 years or greater * Symptomatic low ejection fraction heart failure (weak heart muscle) * Receiving any dose of a beta blocker for the treatment of HF (unless not able to tolerate) * Kidney function not more than mild or moderately impaired * High blood potassium (\>5.0 mEq/L) currently while receiving medications for heart failure OR normal blood potassium currently but previously had high potassium in the12 months prior to screening which caused a permanent reduction or discontinuation of heart failure medications * Hospitalization for heart failure or treatment in an out patient setting with intravenous medications within the last 12 months before screening.
Exclusion criteria
* Current acute decompensated HF, within 4 weeks before screening. Subjects with a discharge from a hospitalization for acute decompensation of HF longer than 4 weeks before screening may be included * Significant primary aortic or mitral valvular heart disease (except secondary mitral regurgitation due to left ventricular dilatation) * Heart transplantation or planned heart transplantation (i.e., currently on a heart transplant waiting list) during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Serum K+ Levels From Baseline | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | Adjusted mean changes in serum K+ from Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | From Day 1/Baseline to week 90 | Cumulative incidence of the first event of hyperkalemia with a serum K+ value \>5.5 mEq/l taking death as competing and calculated as CIF Estimates (95% CI) over time. Aalen-Johansen estimators of the cumulative incidence function with death as a competing event. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter |
| CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | From Day 1/Baseline to week 102 | Cumulative incidence of the reduction of the MRA dose below target dose calculated as CIF Estimates (95% CI) over time. Note: The reduction below the MRA target dose must last for at least 14 days (orless if at the end of study) to confirm this endpoint. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter |
| Investigator-reported Events of Hyperkalemia | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | Participant's follow-up is from the date of the first dose of randomized study medication up to the participant's end of study date or 24 Jun 2021, whichever comes first. Annualized event rate per 100 subject-years= The total number of events for all subjects in the treatment group divided by the total subject-years of follow-up in that treatment group multiplied by 100. |
| Hyperkalemia-related Hard Outcomes Endpoints | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | Analyzed using Win Ratio approach with the following hierarchical components: 1. Time to CV death 2. Total number of CV hospitalizations 3. Total number of hyperkalemia toxicity events with serum K+ \>6.5 mEq/l 4. Total number of hyperkalemia events with serum K+ \>6.0-6.5 mEq/l 5. Total number of hyperkalemia events with serum K+ \>5.0 mEq/l MHTE=More hyperkalemia toxicity events; MHE=More hyperkalemia events; CV=Cardiovascular |
| RAASi Use Score | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | RAASi use score (0 to 8 points) analyzed using the Win Ratio approach for each pair of participants with the following additive components: 1. All-cause death 2. Occurrence of a CV hospitalization 3. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) a MRA, and iii) a beta-blocker Each participant in each comparison can have 0-8 points and all participants are compared using this score at the respective appropriate follow-up time point. RAASi=renin-angiotensin-aldosterone system inhibitor; ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNi=angiotensin receptor/neprilysin inhibitor; MRA=mineralocorticoid receptor antagonist. |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Czechia, France, Georgia, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Russia, Serbia, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
From a total of 1642 screened participants, 1195 entered the Run-in Phase. The Run-in Phase Set includes participants who signed the informed consent and received at least 1 dose of patiromer during the Run-in Phase but were not eligible to be randomized. A total of 1168 participants received patiromer during Run-in Phase, and 878 of these participants were randomized to receive patiromer or placebo during the Treatment Phase
Participants by arm
| Arm | Count |
|---|---|
| Patiromer Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase.
The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). | 439 |
| Placebo Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase.
The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). | 439 |
| Total | 878 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Run-in Phase | 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 10 | 0 |
| Run-in Phase | 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L | 6 | 0 |
| Run-in Phase | AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | AE; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L | 2 | 0 |
| Run-in Phase | AE (Adverse Event) | 17 | 0 |
| Run-in Phase | AE; Physician Decision | 1 | 0 |
| Run-in Phase | AE; Withdrawal By Subject | 3 | 0 |
| Run-in Phase | AE; Withdrawal By Subject; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Death | 1 | 0 |
| Run-in Phase | Exceeded 12 Weeks Of Run In | 2 | 0 |
| Run-in Phase | Non-Compliance With Study Drug | 2 | 0 |
| Run-in Phase | Not treated with Patiromer during Run-in | 27 | 0 |
| Run-in Phase | Physician Decision | 1 | 0 |
| Run-in Phase | Protocol Violation | 13 | 0 |
| Run-in Phase | Randomization Crit #1, #4; Withdraw By Subject; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criteria #1, #2 | 5 | 0 |
| Run-in Phase | Randomization Criteria #1, #2 #4; AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criteria #1, #3 | 1 | 0 |
| Run-in Phase | Randomization Criteria #1, #4 | 1 | 0 |
| Run-in Phase | Randomization Criteria #1, #4; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criteria #2, #3 | 1 | 0 |
| Run-in Phase | Randomization Criteria #2, #3, #4 | 1 | 0 |
| Run-in Phase | Randomization Criteria #2, #4 | 4 | 0 |
| Run-in Phase | Randomization Criteria #3, #4 | 1 | 0 |
| Run-in Phase | Randomization Criteria #3, #4; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L | 2 | 0 |
| Run-in Phase | Randomization Criterion #1 | 24 | 0 |
| Run-in Phase | Randomization Criterion #1; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 2 | 0 |
| Run-in Phase | Randomization Criterion #1; AE | 4 | 0 |
| Run-in Phase | Randomization Criterion #1; AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criterion #2 | 5 | 0 |
| Run-in Phase | Randomization Criterion #3 | 11 | 0 |
| Run-in Phase | Randomization Criterion #3; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criterion #3; Exceeded 12 Weeks Of Run In | 1 | 0 |
| Run-in Phase | Randomization Criterion #3; Physician Decision | 1 | 0 |
| Run-in Phase | Randomization Criterion #4 | 3 | 0 |
| Run-in Phase | Randomization Criterion #4; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L | 2 | 0 |
| Run-in Phase | Randomization Criterion #4; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L | 1 | 0 |
| Run-in Phase | Randomization Criterion #4; AE | 4 | 0 |
| Run-in Phase | Randomization Criterion #4; AE; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L | 1 | 0 |
| Run-in Phase | Sponsor Request | 34 | 0 |
| Run-in Phase | Study Terminated By Sponsor | 71 | 0 |
| Run-in Phase | Withdrawal by Subject | 43 | 0 |
| Run-in Phase | Withdrawal By Subject; Withdrawal Of Consent | 1 | 0 |
| Run-in Phase | Withdrawal Of Consent | 1 | 0 |
| Treatment Phase (Overall Study) | Adverse Event | 27 | 21 |
| Treatment Phase (Overall Study) | Consent withdrawn by subject | 21 | 25 |
| Treatment Phase (Overall Study) | Delayed visit and insufficient study | 6 | 6 |
| Treatment Phase (Overall Study) | Early study termination | 0 | 1 |
| Treatment Phase (Overall Study) | End of study visit not completed/delayed | 1 | 3 |
| Treatment Phase (Overall Study) | Lost to Follow-up | 1 | 0 |
| Treatment Phase (Overall Study) | Physician Decision | 20 | 13 |
| Treatment Phase (Overall Study) | Protocol Violation | 0 | 1 |
| Treatment Phase (Overall Study) | Sponsor's decision | 1 | 0 |
| Treatment Phase (Overall Study) | Treatment discontinuation | 2 | 2 |
Baseline characteristics
| Characteristic | Patiromer | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 258 Participants | 528 Participants | 270 Participants |
| Age, Categorical Between 18 and 65 years | 181 Participants | 350 Participants | 169 Participants |
| Age, Continuous | 66.6 years STANDARD_DEVIATION 10 | 66.9 years STANDARD_DEVIATION 10 | 67.1 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 56 Participants | 113 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 381 Participants | 760 Participants | 379 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Argentina | 16 participants | 32 participants | 16 participants |
| Region of Enrollment Belgium | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Brazil | 6 participants | 16 participants | 10 participants |
| Region of Enrollment Bulgaria | 43 participants | 91 participants | 48 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Czechia | 2 participants | 9 participants | 7 participants |
| Region of Enrollment France | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Georgia | 139 participants | 257 participants | 118 participants |
| Region of Enrollment Germany | 4 participants | 6 participants | 2 participants |
| Region of Enrollment Hungary | 8 participants | 19 participants | 11 participants |
| Region of Enrollment Israel | 8 participants | 12 participants | 4 participants |
| Region of Enrollment Italy | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Mexico | 6 participants | 10 participants | 4 participants |
| Region of Enrollment Netherlands | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Poland | 37 participants | 80 participants | 43 participants |
| Region of Enrollment Russia | 37 participants | 79 participants | 42 participants |
| Region of Enrollment Serbia | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Spain | 11 participants | 25 participants | 14 participants |
| Region of Enrollment Ukraine | 81 participants | 156 participants | 75 participants |
| Region of Enrollment United States | 30 participants | 62 participants | 32 participants |
| Sex: Female, Male Female | 112 Participants | 238 Participants | 126 Participants |
| Sex: Female, Male Male | 327 Participants | 640 Participants | 313 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 439 | 18 / 439 |
| other Total, other adverse events | 320 / 439 | 325 / 439 |
| serious Total, serious adverse events | 54 / 439 | 58 / 439 |
Outcome results
Primary
Changes in Serum K+ Levels From Baseline
Adjusted mean changes in serum K+ from Baseline.
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Changes in Serum K+ Levels From Baseline | 0.029 Milliequivalents Per Liter (mEq/l) | Standard Error 0.019 |
| Placebo | Changes in Serum K+ Levels From Baseline | 0.127 Milliequivalents Per Liter (mEq/l) | Standard Error 0.019 |
Comparison: Difference in adjusted mean changes (SE)p-value: <0.00195% CI: [-0.128, -0.067]Mixed model for repeated measures (MMRM)
Secondary
CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time
Cumulative incidence of the reduction of the MRA dose below target dose calculated as CIF Estimates (95% CI) over time. Note: The reduction below the MRA target dose must last for at least 14 days (orless if at the end of study) to confirm this endpoint. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter
Time frame: From Day 1/Baseline to week 102
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 18 | 0.10 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 54 | 0.19 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 6 | 0.06 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 66 | 0.22 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 30 | 0.14 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 78 | 0.27 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 2 | 0.03 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 90 | 0.27 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 42 | 0.16 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 102 | 0.27 Probability |
| Patiromer | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 1 | 0.02 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 102 | NA Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 1 | 0.04 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 2 | 0.08 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 6 | 0.12 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 18 | 0.15 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 30 | 0.19 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 42 | 0.23 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 54 | 0.26 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 66 | 0.27 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 78 | 0.29 Probability |
| Placebo | CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | Week 90 | 0.29 Probability |
Comparison: Hazard Ratio patiromer vs placebo.~The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR.~HR = Hazard Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration ratep-value: =0.00695% CI: [0.45, 0.87]Regression, Cox
Secondary
CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time
Cumulative incidence of the first event of hyperkalemia with a serum K+ value \>5.5 mEq/l taking death as competing and calculated as CIF Estimates (95% CI) over time. Aalen-Johansen estimators of the cumulative incidence function with death as a competing event. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter
Time frame: From Day 1/Baseline to week 90
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 1 | 0.02 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 2 | 0.04 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 6 | 0.05 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 18 | 0.08 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 30 | 0.13 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 42 | 0.17 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 54 | 0.21 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 66 | 0.25 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 78 | 0.30 Probability |
| Patiromer | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 90 | 0.34 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 66 | 0.34 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 1 | 0.04 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 42 | 0.24 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 2 | 0.08 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 90 | 0.34 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 6 | 0.10 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 54 | 0.29 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 18 | 0.14 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 78 | 0.34 Probability |
| Placebo | CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | Week 30 | 0.20 Probability |
Comparison: Hazard Ratio patiromer vs placebo.~The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR.~HR = Hazard Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration ratep-value: =0.00695% CI: [0.45, 0.87]Regression, Cox
Secondary
Hyperkalemia-related Hard Outcomes Endpoints
Analyzed using Win Ratio approach with the following hierarchical components: 1. Time to CV death 2. Total number of CV hospitalizations 3. Total number of hyperkalemia toxicity events with serum K+ \>6.5 mEq/l 4. Total number of hyperkalemia events with serum K+ \>6.0-6.5 mEq/l 5. Total number of hyperkalemia events with serum K+ \>5.0 mEq/l MHTE=More hyperkalemia toxicity events; MHE=More hyperkalemia events; CV=Cardiovascular
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | CV death in Placebo Group First | 3491 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | CV death in Patiromer Group First | 4609 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | More CV hospitalizations in Placebo Group | 4539 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | More CV hospitalizations in Patiromer Group | 4178 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHTE with serum K+>6.5 in Placebo Group | 419 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHTE with serum K+>6.5 in Patiromer Group | 401 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHE with serum K+>6.0-6.5 in Placebo Group | 4283 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHE with serum K+>6.0-6.5 in Patiromer Group | 1446 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHE with serum K+>5.0-6.0 in Placebo Group | 55633 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | MHE with serum K+>5.0-6.0 in Patiromer Group | 34156 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | None of the above | 79566 Events |
| Patiromer | Hyperkalemia-related Hard Outcomes Endpoints | Total number of pairs | 192721 Events |
Comparison: Win ratio for composite.~Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers.p-value: <0.00195% CI: [1.231, 1.906]Win Ratio
Comparison: Win ratio CV death and hospitalization.~Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.p-value: =0.74495% CI: [0.526, 1.578]Win Ratio
Secondary
Investigator-reported Events of Hyperkalemia
Participant's follow-up is from the date of the first dose of randomized study medication up to the participant's end of study date or 24 Jun 2021, whichever comes first. Annualized event rate per 100 subject-years= The total number of events for all subjects in the treatment group divided by the total subject-years of follow-up in that treatment group multiplied by 100.
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Investigator-reported Events of Hyperkalemia | 82.38 Ann. event rate per 100 subject-years |
| Placebo | Investigator-reported Events of Hyperkalemia | 114.65 Ann. event rate per 100 subject-years |
Comparison: NBMAC Annualized event RR patiromer vs placebo.~NBMAC adjusted for geographical region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR. Rate ratio less than 1 favors patiromer.~NBMAC=Negative binomial model adjusted for covariates; RR=Rate Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration ratep-value: <0.00195% CI: [0.534, 0.81]Negative binomial model adjusted for cov
Secondary
RAASi Use Score
RAASi use score (0 to 8 points) analyzed using the Win Ratio approach for each pair of participants with the following additive components: 1. All-cause death 2. Occurrence of a CV hospitalization 3. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) a MRA, and iii) a beta-blocker Each participant in each comparison can have 0-8 points and all participants are compared using this score at the respective appropriate follow-up time point. RAASi=renin-angiotensin-aldosterone system inhibitor; ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNi=angiotensin receptor/neprilysin inhibitor; MRA=mineralocorticoid receptor antagonist.
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patiromer | RAASi Use Score | Number of wins in Patiromer Group | 62073 Events |
| Patiromer | RAASi Use Score | Number of wins in Placebo Group | 49733 Events |
| Patiromer | RAASi Use Score | Number of ties | 80915 Events |
| Patiromer | RAASi Use Score | Total number of pairs | 192721 Events |
Comparison: Win ratio for composite.~Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.p-value: =0.04895% CI: [1.003, 1.564]Win Ratio